There has been a considerable effort devoted to the development of new and more versatile polymeric architectures with specific and predictable properties to be used as targeted drug delivery systems. Such desirable features in these materials include: adjustable molecular weights (higher molecular weight (MW), to enhance passive targeting by the Enhanced Permeability and Retention (EPR) effect), predictable structure and conformation in solution, lower heterogeneity, and greater possibility for multivalency. Nevertheless, the design and synthesis of new polymeric constructs of relevant MW, together with their physicochemical characterization, conformational studies, and especially their potential for biological applications still remain to be fully exploited in this area. To this aim, polypeptide-based architectures can be considered suitable aspirants.
Star polypeptides are branched polymers, which consist of various linear chains linked to a central core. There are two main synthetic strategies described: the core-first approach (or multifunctional initiators or divergent approach) and the arm-first approach (or the use of multifunctional linking agents, or convergent approach). Various polypeptide-based star polymers have been synthesized over the years. For example, Klok et al. (Journal of Polymer Science Part A: Polymer Chemistry 2001, 39, (10), 1572-1583) used perylene derivatives with four primary amine groups as initiators to lead 4-arm poly(gamma-benzyl-L-glutamate) (PBLG) and poly(epsilon-benzyloxy-carbonyl-L-lysine) (PZLL) and Inoue et al. (Macromolecular Bioscience 2003, 3, (1), 26-33) used hexafunctional initiators for the synthesis of 6-arm PBLG star polymers both taking profit of the Ring Opening Polymerization (ROP) of N-Carboxyanhydrides (NCAs) techniques. Other examples are provided from the work of Aliferis et al. (Macromolecular Symposia 2006, 240, (1), 12-17) who used 2-(aminomethyl)-2-methyl-1,3-propanediamine as a trifunctional initiator for the synthesis of Poly(epsilon-carbobenzoxy-L-lysine-block-γ-benzyl-L-glutamate), P(BLL-b-BLG)3 3-arm star-block co-polypeptides; or the studies of Karatzas et al. (Reactive and Functional Polymers 2009, 69, (7), 435-440) in the synthesis of 4-arm poly(ethylene oxide)-block-poly(y-benzyl-L-glutamate) (PEO-b-PBLG) hybrid star block co-polymers using 4-arm PEO stars end-functionalized with primary amines as initiators for the polymerization of gamma-Benzyl-L-Glutamate NCA (BLG-NCA) among others. Besides these two widely used approaches, a latest classification takes into account a new synthetic strategy. This approach consists on the reaction of living macroinitiators (MI) (also named macromonomers) with multifunctional molecules acting as cross-linkers giving rise to star-shaped architectures known as core cross-linked star (CCS) polymers (Chen et al. Macromolecular Rapid Communications, 2013, 34, 1507)
One of the most appealing properties, apart from their rheological characteristics and thermoplastic character, is their self-assembly behavior that can be promoted in solution by the presence of functional moieties along the chain arms (in the case of homopolymers) or by using selective solvents (in the case of star-blocks or miktoarm stars). Micellar structural parameters such as critical micellar concentration (CMC), aggregation number, core and shell dimensions, overall micelle concentration as well as thermodynamics and kinetics of micellization of complex structures, such as star-block copolymers and miktoarm stars, have been poorly investigated if compared to linear analogues. In general basis, star structures have higher CMC values and consequently, lower aggregation numbers than their linear block copolymers counterparts.
Overall, it is well-known that macromolecular architecture is a key parameter for the tuning of micellar behavior and properties, and thus, it must be well-considered for the design of new materials and their potential biological applications, in particular as drug delivery systems.
Moreover, despite the growing interest in the development of hybrid and peptide-based star polymers as prospective advanced materials for biological applications, only recently, they have been explored as drug delivery systems. For instance, Sulistio et al. (Chem. Commun, 2011, 47, 1151-1153), synthesized highly functionalized water soluble core cross-linked star (CCS) polymers having degradable cores synthesized entirely from amino acid building blocks which are capable of encapsulating water-insoluble drugs. These types of stars were able to entrap hydrophobic drugs, such as the anti-cancer drug pirarubicin, through physical interactions with pyrene moieties of the core. Moreover, due to the presence of disulfide bonds at the core, the stars could also be cleaved by reducing agents such as dithiothreitol, yielding redox-sensitive polymers.